3,11-diketo-4-bromo-17(beta)-hydroxy-20,21-diacetoxypregnane



it relates to novel compounds useful as inter- 5 Patented Dec. 27, .19491 UNITED STATES PATENT OFFICE 3,11-DIKETO-4-BROMO-17 (f3) -HYDROXY-20,21-DIACETQXXPBEGNAN E Lewis 11. Sarett, Prineeton, N .L assignor toMerck & 00., Inc., Ra lway, N. J., a corporation of New Jersey NoDrawing. Original application July 14, 1945, Serial No. 605,194. Dividedand this application February 23, 1946, Serial No. 649,767

' 1 Claim. (Cl. 260--397.4) l .2 This invention is concerned generallywith structural formulae the former configuration is novel chemicalcompounds of the cyclopentanoshown by writing the -17 substituent(hydroxyl) dimethylpolyhydrophenanthrene series and to to the right ofthe C17 carbon side chain, thus processes of preparing same; moreparticularly CHOH mediates in the synthesis of the adrenal cortical S 0Hhormone A 4,5-3,1l,20-triketo-l7(fi), 21-dihydroxy pregnene. Thisapplication is a divisional of amending application Serial 6059194 medin the latter case above the side chain, thus July 14, 1945, nowabandoned. 1"0

This hormone is known to occur naturally in 0H CH=CHI the adrenalcortex; it has the structural formula:

l 3. The stereochemical relationship of rings A 2o( ;=0 and B isindicated in the formulae by a solid line 0 g Q J representing thevalence bond in the cis config- E uration.

C In accordance with the presentinvention it is 1g: g I I g 1 new foundthis hormone can be synthesized by /1\ /9\ reactions indicated asfollows: 3,02 10 so OH, CH:

A B 0=L3 /5 7 H3 HrCOgH v J}H.CO,H

0 (standard numbering of C-positions) 803mg 0\ This formula, forpurposes of convenience, is Kent CHI hereinafter reproduced below in theabbreviated form: 80

CHzOH H0 R0 I =0 H cal 0H I 11 as u Egg CH: reagent CHI (3H1 oil-comCH-COX o 40 7 CH: CH:

o o In the following description of the invention, CH the stereochemicalrelationship of substituents are indicated by the following conventions:

1. A substituent at the C-3 position which is trans to the C-10 methylgroup is parenthetically R0 R0 designated (a).

2. A substituent at the C-17 position, the stereo- H H chemicalconfiguration of which is identical with J IV III that of the naturallyoccurring adrenal hormones, is parenthetically designated (3); the lepimeric configuration is designated (a). In the guano CHI n CH: 0: no Am O by docan 0 flan I.

VII

lhidmhdl CH==OB X111 XIV lcylnting 81011! a m l H OH O CH CH=CH on I onh-I- halogenaflng agent.

' xvl' xv cn-cmx' ca-cmon" OH: CB

OH MOB" CH 65 I XVII XVI B! R! CHO hydrolyfll OH 60 H H GH-CHaOB"CH-CHsOH 5 OH CH o\ Rlllon "')|0 CH '10 xx x m y n no orr-omon cn-cmonon on Y hydrol- OK yais XXI XX OHIOH Juror! cn-omolv'" OH: OH (3 h 3?"area 01! XXIII 0 acylating agent cmoa cmoaw n 0 an H o R!!!" 0H OH OH oi R Q 4 OH -x" CH XXV XXIV H II CH'O n"!!! 0 R o R!!!" H o R!!!" H 0Kill];

0 0H Cm 0H --e pyridine CH:

' xxvr l hydro CHOB CHQOH non (m-on OH OH 1 CHil 0H 1-' (R)a0 CB: 0U

XXVII In the above formulae, R, R, R", R', R"" R""', and R are acyl; X,X and X" are halogen, and M is an alkali metal or an alkaline earthmetal /2.

The reactions above indicated are conducted 7 nitrous acid, a mixturecontaining predomi-- nantly A "-=-3-acyloxy-ll-keto-pregnene (VI) and A-S-acyIoxy-ll-keto-pregnene (VII) and a minor amount of3-acyloxy-11-keto-20-hydrcxypregnane (VIII) results. The proportion ofthe desired compound (VI) present m this mixture can be increased bytreating the mixture with an aromatic sulfonyl halide followed byfurther treatment with a base to cause removal of the elements of thecorresponding aromatic sulfonic acid. The mixtur 'of these compounds(VI) and (VII) or of (VI), (VII) and (VIII), is then treated with ozonefollowed by decomposition of the'ozonide, producing 3-acyloxy-l1,17-

diketoetiocholane (IX) and 3-acyloxy-ll -ketol7-formyletiocholane (X).Compound (X) is oxidized to 3-acyloxy-ll-ketoetiocholanic acid (XI)which is separated from compound (IX) by extraction with alkali.

Compound. (IX) is hydrolyzed I to form3-hydroxy-l1,1'7-diketoetiochlo1ane (XII) which is treated withacetylene to form 3,17-dihydroxyll-keto-pregnine-20 (XIII). Thiscompound (XIII) is catalyticallyhydrogenated to produce 7 A 8,17dihydoxy 11 ketopregnene (XIV) which is acylated to form A=-*-3-acyloxy-17- hydroxy-ll-ketopregnene (XV), and this compound ishalogenated to produce A -s-acyloxyll-keto-zl-halopregnene (XVI). withan'alkali metal salt or alkaline earth metal salt of an organic acid,this compound yields A "-?-3,2 1-diacy1oxy-ll-ketopregnene (XVII) whihishydrolyzed producing A -3,21-dihydroxy-ll-ketopregnene (XVIII). Thelatter product (XVIII) is partially esteriiled and the mono ester (XIX)thus produced is oxidized to convert the unesterified hydroxy group inthe 3 position to a keto group, thereby yielding the ester of A-3,11-diketo-21-acyloxy-pregnene (XX). This product (XX) is hydrolyzedand the Ai'w-3,11-dlketo-2l-hydroxypregnene (XXI) thus formed isacylated producing A JO-3,11-d1- keto-2l-acyloxypregnene (XXII).Hydroxylation at the unsaturation of the last mentioned compound (XXII)results in the production of 3,11-

diketo-l'l (p) ,20,21-trlhydroxypregnene (XXIII) which is then acylatedto form 3,11-diketo-17 (p) hydroxy 20,21 diacyloxypregnene Whenbrominated, this compound yields 3,1l-diketo 4 bromo 17(5) hydroxy 20,21diacyloxypregnene (XXV).

This compound is then treated with a reagent capable of removing theelements of hydrogen bromide, thereby producing A -3,11-diketo- 17(5)-hydroxy-20,21-diacyloxypregnene (XXVI) which on hydrolysis for-ms A-3,11-diketo-17() 20,21-trihydroxypregnene (XXVII). Partial acylation ofthis compound (XXVII) gives A- 3,l1 diketo 17(5) ,20 dihydroxy 21acyloxypregnene (XXVIII) which, when oxidized, yields a mixture ofA*--3,11,20-triketo-1.'I(,6)-hydroxy- 2l-acyloxypregnene (XXIX) and M'-3,11,17- triketo androstene (XXX). Compounds (XXIX) and (XXX) may beseparated by conventional operations, for example chromatography, andcompound (XXIX) hydrolyzed to produce the desired adrenal hormone, A-3,l1,20-triketo- 17(3) ,21-dihydroxypregnene.

This invention is concerned with compounds of the type represented byintermediate 25 above and also with processes of producing same,together with certain related compounds such as intermediates 26 and 21.Intermediate 25 may be represented by the formula:

cmoa

non on; on

in which R is acyl.

The starting material employed in the process according to thisinvention, 3,11-diketo-l'I-hydroxy-20,2l-diacyloxypregnane, may beobtained as described in copending application Serial No. 649,766, filedFebruary 23, 1946.

In accordance with this invention, the compound 3,1ldiketo-17-hydroiw-20,21-diacycloxypregnane is reacted with anequimolecular quantity of bromine in an inert solvent such as glacialacetic acid, the bromine entering molecule at the when treated (xxrv).

4 position to form 4-bromo-3,1l-diketo-l7-hydroxy-20,21-diacyloxypregnane. It is important not to use more than anequimolecular quantity of bromine because the use of an excess favorsthe formation of the dibromide. This product is treated thereafter, forexample by refluxing, with a tertiary amine, e. g. pyridine, causing theformation of a double bond in the desired 4-5 position, thus yielding A-3,1141- keto-17-hydroxy-20,2l-diacyloxypregnene, having the structuralformula:

CHsOB CHsOH (EH03.

CH] CH This compound is considered to be one of the substances whichoccur naturally in the adrenal cortex.

The acyl group R" in the above formulae may be any desired groupderived, for example, from acetic, propionic, butyric, valeric, caproic,capric, etc., benzoic, toluic, or phenylacetic acid, of which the loweraliphatic acids, 1. e. those having 6 carbon atoms or less, arepreferred.

Preferably, the 3,11-diketo-17-hydroxy-203ldiacyloxypregnane is reactedwith bromine in an inert solvent such as glacial acetic acid, followingwhich the product is isolated by taking the reac- Example To a solutionof 126 mg. of 3,11-diketo-1'l (p)- hydroxy-20,2l-diacetoxypregnane in .5cc. of glacial acetic acid was added a solution of 42.3 mg. of brominein .5 cc. of glacial acetic acid. After a few minutes decolorationensued, the mixture was taken up in-ether, washed with dilute sodiumbicarbonate and water, concentrated in vacuo,

and crystallized from a small volume of ether. The4-bromo-3,1l-diketo-17 (p)-hydroxy-20,21-

diacetoxypregnane so obtained in about 90% yieldhad a melting point of188-189 C. Other compounds of this type having acyl groups difierentfrom acetyl react with bromine under these conditions to yield analogousproducts.

A solution of 124 mg. of the 4-bromo compound was refluxed in 15 cc. ofpyridine for hours, cooled, concentrated in vacuo, diluted with water,and extracted with chloroform. The chloroform layer was washed withdilute hydrochloric acid, then with water, and concentrated to drynessin vacuo. The residue was dissolved in a small volume of benzene andintroduced into a column containing 3 grams neutral alumina previouslyactivated at 150 C. The elution from thiscolumn of the desired compoundwas carried out by addition thereto of cc. portions of solventsbeginning with absolute ether, proceeding through ether-chloroformmixtures with an increasing proportion of chloroform, through purechloroform, then through chloroform-acetone mixtures, and finally withmethanol. The zl-monoacetate was contained in the fractions from 4:1chloroform: ether to 1:1 chloroform acetone. The product so obtained, A-3,11-diketo-17 (p)-hydroxy-20,21-diacetoxypregnene, on crystallizationfrom methanol had a melting point of 252-253.5 C. (a) -|-1'79. Apractically 40% yield was thus obtained.

To a solution of 360 mg. of A -3,11-diketo-17 (p)-hydroxy-20,2l-diacetoxypregnene in 20 cc. of methanol was added asolution of 150 m8. of potassium carbonate and 250 mg. of potassiumbicarbonate in 5 cc. of water. The mixture was permitted to stand atroom temperature overnight, was concentrated in vacuo, and extractedwith chloroform. The chloroform solution was washed with water,concentrated in vacuo, and the residue crystallized from acetone. The A3,11-diketo-17 (p) -20,21-trihydroxypregnene so obtained in about 95%yield had a melting point of 208.5-209.5 (a) +140'.

The temperatures mentioned in the example are room temperatures unlessotherwise indicated. The temperatures, however, are not critical and thereactions may be carried out at higherv or lower temperatures; butextremely high temperatures should be avoided because of the likelihoodof decomposition of the desired products which may result from operationat such temperatures.

Unless otherwise stated, the reagents can be used in diiferentproportions than are indicated in the above example as the proportionsunless otherwise indicated are not critical, although enough of thereagents should be employed to insure substantially complete reaction toproduce the desired products.

The specific rotations for A -3,11-diketo-17(p)-hydroxy-20,21-diacetoxypregnene and A 3,11-diketo-17 (5),20,21-trihydroxypregnene indicated above by the symbol [oz] weredetermined in acetone solution using the D line of sodium.

Various changes and modifications might be made in my invention asdefined herein without departing from the scope thereof. It is myintention that these changes and modifications, to the extent that theyare comprehended within the scope of the appended claims, shall beconsidered as part of my invention.

What is claimed is:

3,11-diketo-4-bromo-17 (p) -hydroxy-20,21-diacetoxypregnane.

LEWIS H. SARE'I'I'.

REFERENCES CITED The following references are of record in the flle ofthis patent:

UNITED STATES PATENTS Number Name Date 40 2,153,700 Serini Apr. 11, 19392,256,500 Serini Sept. 23, 1941 2,345,711 Marker Apr. 4, 1944

